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Simple Summary: Men with metastatic castration-resistant prostate cancer (mCRPC) have shorter overall survival and resist therapy faster if their blood have a poor lipid profile. This poor lipid profile includes high levels of sphingolipids, thus reducing these sphingolipids may slow prostate cancer growth. The aim of our study is to determine if simvastatin can change a poor lipid profile (high sphingolipids) into a better profile (low sphingolipids) in mCRPC. Twenty-seven men with mCRPC were given simvastatin together with their standard treatment for 12 weeks. We found that 11 men had the poor lipid profile at the start of the study. After 12 weeks of treatment, 40% of these 11 men no longer had the poor lipid profile and their sphingolipids were reduced, regardless of changes in their blood cholesterol, LDL or triglycerides. In conclusion, simvastatin can modify the poor lipid profile in some men with mCRPC. Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23–52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate. [ABSTRACT FROM AUTHOR]

Simple Summary: Lipids (fatty substances) and cytokines are molecules that affect how the immune response works. The measurement of the amounts of lipids and cytokines in blood might give clues about how prostate cancers grow or respond to treatment. This study looked at the blood levels of lipids and cytokines in men with advanced prostate cancer that was growing despite standard treatment (metastatic castration-resistant prostate cancer, mCRPC). We found that certain lipids were consistently associated with poorer clinical outcome, while cytokines were not. The levels of a type of lipid (ceramide) were associated with some cytokines. This lipid is known to activate the immune system and is associated with poor outcomes in mCRPC. A change in lipid profiles was associated with better response to treatment. Overall, our findings suggest that blood lipids might be more informative than cytokines, might influence the immune response, and might help predict treatment response. Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients. [ABSTRACT FROM AUTHOR]